Airborne exposure to organic dusts and certain microbial agents is known to cause hypersensitivity pneumonitis (HP) in humans and animals, but not all exposed individuals develop the disease. As a model for HP we expose, via the nasal rout e, a number of different, genetically characterized, inbred mouse strains to the soluble antigens of Thermoactinomyces vulgaris. These antigens are known to induce HP in many species. On the basis of lung pathology these strains have been identified as susceptible or resistant to the disease. The key humoral and cellular parameters of the immune response will be extensively measured and compared among the mouse strains to explain pathogenesis of susceptibility. In preliminary studies we have identified a role for MHC class II genes in regulating susceptibility to HP. Using MHC knockout and transgenic mice we will examine the genetic regulation of susceptibility by MHC genes. Exposure of mice to isolated antigenic components will help to determine relevant antigens and antigen presentation mechanisms in HP. The long range goals of the project are to identify the genes which influence the development of HP in sensitive individuals and to characterize immune regulation as it differs among mouse strains that vary in severity of HP following exposure.